Kennedy’s Disease

Clinical Significance of Tandem Repeats in the Androgen Receptor
  • Jeffrey D. ZajacEmail author
  • Mark Ng Tang Fui
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


Kennedy’ s disease (KD) or spinobulbar muscular atrophy is a hereditary X-linked, progressive neurodegenerative condition caused by an expansion of the CAG triplet repeat in the first exon of the androgen receptor gene. The phenotype in its full form is only expressed in males and presents as weakness and wasting of the upper and lower limbs and bulbarmuscles associated with absent reflexes. Sensory disturbances are present. Various endocrine abnormalities including decreased fertility and gynecomastia are common and amongst the first features of KD. Animal models of KD have demonstrated improvement on withdrawal of testosterone, indicating that this agonist of the androgen receptor is required for the toxic effect. Potential therapies based on testosterone withdrawal in humans have shown some promise, but efficacy remains to be proven. Potential clinical factors, pathogenesis and future approaches to therapy are reviewed in this chapter.


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  1. 1.
    MacLean HE, Warne GL, Zajac JD. Spinal and bulbar muscular atrophy: androgen receptor dysfunction caused by a trinucleotide repeat expansion. J Neurol Sci 1996; 135(2):149–157.PubMedCrossRefGoogle Scholar
  2. 2.
    Lund A, Udd B, Juvonen V et al. Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world. Eur J Hum Genet 2001; 9(6):431–436.PubMedCrossRefGoogle Scholar
  3. 3.
    Chahin N, Klein C, Mandrekar J et al. Natural history of spinal-bulbar muscular atrophy. Neurology 2008; 70(21):1967–1971.PubMedCrossRefGoogle Scholar
  4. 4.
    MacLean HE, Choi WT, Rekaris G et al. Abnormal androgen receptor binding affinity in subjects with Kennedy’s disease (spinal and bulbar muscular atrophy). J Clin Endocrinol Metab 1995; 80(2):508–516.PubMedGoogle Scholar
  5. 5.
    Atsuta N, Watanabe H, Ito M et al. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain 2006; 129(Pt 6): 1446–1455.PubMedCrossRefGoogle Scholar
  6. 6.
    Hanajima R, Terao Y, Nakatani-Enomoto S et al. Postural tremor in X-linked spinal and bulbar muscular atrophy. Mov Disord 2009; 24(14):2063–2069.PubMedCrossRefGoogle Scholar
  7. 7.
    Sperfeld AD, Hanemann CO, Ludolph AC et al. Laryngospasm: an underdiagnosed symptom of X-linked spinobulbar muscular atrophy. Neurology 2005; 64(4):753–754.PubMedCrossRefGoogle Scholar
  8. 8.
    Dejager S, Bry-Gauillard H, Bruckert E et al. A comprehensive endocrine description of Kennedy’s disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab 2002; 87(8):3893–3901.PubMedGoogle Scholar
  9. 9.
    Zajac JD, MacLean HE. Kennedy’s disease: clinical aspects. In: Wells RD, Warren ST, Sarmiento M, eds. Genetic Instabilities and Hereditary Neurological Diseases. San Diego: Academic Press; 1998:87–100.Google Scholar
  10. 10.
    Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 1968; 18(7):671–680.PubMedGoogle Scholar
  11. 11.
    Lee JH, Shin JH, Park KP et al. Phenotypic variability in Kennedy’s disease: implication of the early diagnostic features. Acta Neurol Scand 2005; 112(1):57–63.PubMedCrossRefGoogle Scholar
  12. 12.
    Kassubek J, Juengling FD, Sperfeld AD. Widespread white matter changes in Kennedy disease: a voxel based morphometry study. J Neurol Neurosurg Psychiatry 2007; 78(11): 1209–1212.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Soragna D, Messa C, Mochi M et al. Dopaminergic pathways involvement in Kennedy’s disease: neurophysiological and. Journal of Neurology 2001; 248(8):710–712.PubMedCrossRefGoogle Scholar
  14. 14.
    Shaw PJ, Thagesen H, Tomkins J et al. Kennedy’s disease: unusual molecular pathologic and clinical features. Neurology 1998; 51(1):252–255.PubMedCrossRefGoogle Scholar
  15. 15.
    Ishihara H, Kanda F, Nishio H et al. Clinical features and skewed X-chromosome inactivation in female carriers of X-linked recessive spinal and bulbar muscular atrophy. J Neurol 2001; 248(10):856–860.PubMedCrossRefGoogle Scholar
  16. 16.
    Schmidt BJ, Greenberg CR, Allingham-Hawkins DJ et al. Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology 2002; 59(5):770–772.PubMedCrossRefGoogle Scholar
  17. 17.
    Johansen JA, Yu Z, Mo K et al. Recovery of function in a myogenic mouse model of spinal bulbar muscular atrophy. Neurobiol Dis 2009; 34(1):113–120.PubMedCrossRefGoogle Scholar
  18. 18.
    Ferrante MA, Wilbourn AJ. The characteristic electrodiagnostic features of Kennedy’s disease. Muscle Nerve 1997; 20(3):323–329.PubMedCrossRefGoogle Scholar
  19. 19.
    Suzuki K, Katsuno M, Banno H et al. CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA. Brain 2008; 131(Pt l):229–239.PubMedCrossRefGoogle Scholar
  20. 20.
    Sobue G, Hashizume Y, Mukai E et al. X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain 1989; 112(Pt l):209–232.PubMedCrossRefGoogle Scholar
  21. 21.
    Harding AE, Thomas PK, Baraitser M et al. X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry 1982; 45(11): 1012–1019.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Li M, Sobue G, Doyu M et al. Primary sensory neurons in X-linked recessive bulbospinal neuropathy: histopathology and androgen receptor gene expression. Muscle Nerve 1995; 18(3):301–308.PubMedCrossRefGoogle Scholar
  23. 23.
    Soraru G, D’Ascenzo C, Polo A et al. Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. Journal of the Neurological Sciences 2008; 264(1–2): 100–105.PubMedCrossRefGoogle Scholar
  24. 24.
    Soukup GR, Sperfeld AD, Uttner I et al. Frontotemporal cognitive function in X’linked spinal and bulbar muscular atrophy (SBMA): a controlled neuropsychological study of 20 patients. Journal of Neurology 2009;256(11):1869–1875.PubMedCrossRefGoogle Scholar
  25. 25.
    Logroscino G, Traynor BJ, Hardiman O et al. Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry 2008; 79(1):6–11.PubMedCrossRefGoogle Scholar
  26. 26.
    McDermott CJ, Shaw PJ. Diagnosis and management of motor neurone disease. BMJ 2008; 336(7645): 658–662.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Corcia P, Meininger V. Management of amyotrophic lateral sclerosis. Drugs 2008; 68(8):1037–1048.PubMedCrossRefGoogle Scholar
  28. 28.
    van der Graaff MM, de Jong JM, Baas F et al. Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: aclinical and brain imagingreview. Neuromuscul Disord 2009; 19(1):53–58.PubMedCrossRefGoogle Scholar
  29. 29.
    Pugdahl K, Fuglsang-Frederiksen A, de Carvalho M et al. Generalised sensory system abnormalities in amyotrophic lateral sclerosis: a European multicentre study. J Neurol Neurosurg Psychiatry 2007; 78(7):746–749.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Amoiridis G, Tsimoulis D, Ameridou I. Clinical, electrophysiologic and pathologic evidence for sensory abnormalities in ALS. Neurology 2008; 71(10):779.PubMedCrossRefGoogle Scholar
  31. 31.
    Suzuki K, Katsuno M, Banno H et al. The profile of motor unit number estimation (MUNE) in spinal and bulbar muscular atrophy. J Neurol Neurosurg Psychiatry 2010; 81(5):567–571.PubMedCrossRefGoogle Scholar
  32. 32.
    La Spada AR, Wilson EM, Lubahn DB et al. Androgen receptor gene mutations in X’linked spinal and bulbar muscular atrophy. Nature 1991; 352(6330):77–79.PubMedCrossRefGoogle Scholar
  33. 33.
    Greenland KJ, Zajac JD. Kennedy’s disease: pathogenesis and clinical approaches. Intern Med J 2004; 34(5):279–286.PubMedCrossRefGoogle Scholar
  34. 34.
    Adachi H, Katsuno M, Minamiyama M et al. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 2005; 128(Pt 3):659–670.PubMedCrossRefGoogle Scholar
  35. 35.
    Li M, Miwa S, Kobayashi Y et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Annals of Neurology 1998; 44(2):249–254.PubMedCrossRefGoogle Scholar
  36. 36.
    Grossmann M, Thomas MC, Panagiotopoulos S et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab 2008; 93(5): 1834–1840.CrossRefPubMedGoogle Scholar
  37. 37.
    MacLean HE, Ball EM, Rekaris G et al. Novel androgen receptor gene mutations in Australian patients with complete androgen insensitivity syndrome. Hum Mutat 2004; 23(3):287.PubMedCrossRefGoogle Scholar
  38. 38.
    Yeh S, Tsai MY, Xu Q et al. Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc Natl Acad Sci USA 2002;99(21):13498–13503.PubMedCrossRefGoogle Scholar
  39. 39.
    Notini AJ, Davey RA, McManus JF et al. Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model. J Mol Endocrinol 2005; 35(3):547–555.PubMedCrossRefGoogle Scholar
  40. 40.
    Mariotti C, Castellotti B, Pareyson D et al. Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord 2000; 10(6):391–397.PubMedCrossRefGoogle Scholar
  41. 41.
    Thomas PS Jr., Fraley GS, Damian V et al. Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X’linked spinal and bulbar muscular atrophy. Hum Mol Genet 2006; 15(14):2225–2238.PubMedCrossRefGoogle Scholar
  42. 42.
    Cary GA, La Spada AR. Androgen receptor function in motor neuron survival and degeneration. Phys Med Rehabil Clin N Am 2008; 19(3):479–494, viii.PubMedCrossRefGoogle Scholar
  43. 43.
    Poletti A, Negri-Cesi P, Martini L. Reflections on the diseases linked to mutations of the androgen receptor. Endocrine 2005; 28(3):243–262.PubMedCrossRefGoogle Scholar
  44. 44.
    Walsh R, Storey E, Stefani D et al. The roles of proteolysis and nuclear localisation in the toxicity of the polyglutamine diseases. A review. Neurotox Res 2005; 7(1–2):43–57.PubMedCrossRefGoogle Scholar
  45. 45.
    McCampbell A, Taylor JP, Taye AA et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 2000; 9(14):2197–2202.PubMedCrossRefGoogle Scholar
  46. 46.
    Minamiyama M, Katsuno M, Adachi H et al. Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 2004; 13(11): 1183–1192.PubMedCrossRefGoogle Scholar
  47. 47.
    Walcott JL, Merry DE. Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J Biol Chem 2002; 277(52):50855–50859.PubMedCrossRefGoogle Scholar
  48. 48.
    Chan HY, Warrick JM, Andriola I et al. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Human Molecular Genetics 2002; 11(23):2895–2904.PubMedCrossRefGoogle Scholar
  49. 49.
    Morfini G, Pigino G, Szebenyi G et al. JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat Neurosci 2006; 9(7):907–916.PubMedCrossRefGoogle Scholar
  50. 50.
    Katsuno M, Adachi H, Minamiyama M et al. Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy. Journal of Neuroscience 2010; 30(16):5702–5712.PubMedCrossRefGoogle Scholar
  51. 51.
    Ellerby LM, Hackam AS, Propp SS et al. Kennedy’s disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J Neurochem 1999; 72(1):185–195.PubMedCrossRefGoogle Scholar
  52. 52.
    Adachi H, Katsuno M, Minamiyama M et al. Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbarmuscularatrophytransgenic mouse modelbyreducingnuclear-localized mutant androgen receptor protein. J Neurosci 2003; 23(6):2203–2211.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Paulson HL, Perez MK, Trottier Y et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 1997; 19(2):333–344.PubMedCrossRefGoogle Scholar
  54. 54.
    Li M, Nakagomi Y, Kobayashi Y et al. Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am J Pathol 1998; 153(3):695–701.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Beitel LK, Scanlon T, Gottlieb B et al. Progress in spinobulbar muscular atrophy research: insights into neuronal dysfunction caused by the polyglutamine-expanded androgen receptor. Neurotox Res 2005; 7(3):219–230.PubMedCrossRefGoogle Scholar
  56. 56.
    Chevalier-Larsen ES, O’Brien CJ, Wang H et al. Castration restores function and neurofilament alterations of aged symptomatic males in atransgenic mouse model of spinal and bulbar muscular atrophy. J Neurosci 2004; 24(20):4778–4786.PubMedCrossRefGoogle Scholar
  57. 57.
    Katsuno M, Banno H, Suzuki K et al. Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9(9):875–884.PubMedCrossRefGoogle Scholar
  58. 58.
    Matsumoto A, Micevych PE, Arnold AP. Androgen regulates synaptic input to motoneurons of the adult rat spinal cord. J Neurosci 1988; 8(11):4168–4176.PubMedCrossRefGoogle Scholar
  59. 59.
    Goldstein LA, Sengelaub DR. Timing and duration of dihydrotestosterone treatment affect the development of motoneuron number and morphology in a sexually dimorphic rat spinal nucleus. J Comp Neurol 1992; 326(1):147–157.PubMedCrossRefGoogle Scholar
  60. 60.
    Watson NV, Freeman LM, Breedlove SM. Neuronal size in the spinal nucleus of the bulbocavernosus: direct modulation by androgen in rats with mosaic androgen insensitivity. J Neurosci 2001; 21(3): 1062–1066.PubMedCrossRefGoogle Scholar
  61. 61.
    Schroder HD, Reske-Nielsen E. Preservation of the nucleus X-pelvic floor motosystem in amyotrophic lateral sclerosis. Clin Neuropathol 1984; 3(5):210–216.PubMedGoogle Scholar
  62. 62.
    Katsuno M, Adachi H, Minamiyama M et al. Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration. Journal of Neuroscience 2006; 26(47):12106–12117.PubMedCrossRefGoogle Scholar
  63. 63.
    Takeyama K, Ito S, Yamamoto A et al. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 2002; 35(5):855–864.PubMedCrossRefGoogle Scholar
  64. 64.
    McManamny P, Chy HS, Finkelstein DI et al. A mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 2002; 11(18):2103–2111.PubMedCrossRefGoogle Scholar
  65. 65.
    Abel A, Walcott J, Woods J et al. Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet 2001; 10(2):107–116.PubMedCrossRefGoogle Scholar
  66. 66.
    Kinirons P, Rouleau GA. Administration of testosterone results in reversible deterioration in Kennedy’s disease. J Neurol Neurosurg Psychiatry 2008; 79(1):106–107.PubMedCrossRefGoogle Scholar
  67. 67.
    Goldenberg JN, Bradley WG. Testosterone therapy and the pathogenesis of Kennedy’s disease (X’linked bulbospinal muscular atrophy). Journal of the Neurological Sciences 1996; 135(2): 158–161.PubMedCrossRefGoogle Scholar
  68. 68.
    Katsuno M, Adachi H, Kume A et al. Testosterone reduction prevents phenotypic expression in atransgenic mouse model of spinal and bulbar muscular atrophy. Neuron 2002; 35(5):843–854.PubMedCrossRefGoogle Scholar
  69. 69.
    Katsuno M, Adachi H, Doyu M et al. Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med 2003; 9(6):768–773.PubMedCrossRefGoogle Scholar
  70. 70.
    Yang Z, Chang YJ, Yu IC et al. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nat Med 2007; 13(3):348–353.PubMedCrossRefGoogle Scholar
  71. 71.
    Tokui K, Adachi H, Waza M et al. 17-DMAGameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse. Human Molecular Genetics 2009; 18(5):898–910.PubMedCrossRefGoogle Scholar
  72. 72.
    Adachi H, Waza M, Tokui K et al. CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model. Journal of Neuroscience 2007; 27(19):5115–5126.PubMedCrossRefGoogle Scholar
  73. 73.
    Palazzolol, Stack C, Kong L et al. Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Neuron 2009; 63(3):316–328.CrossRefGoogle Scholar
  74. 74.
    Banno H, Katsuno M, Suzuki K et al. Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Annals of Neurology 2009; 65(2):140–150.PubMedCrossRefGoogle Scholar
  75. 75.
    Shahani S, Braga-Basaria M, Basaria S. Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J Clin Endocrinol Metab 2008; 93(6):2042–2049.PubMedCrossRefGoogle Scholar
  76. 76.
    Greenspan SL. Approach to the prostate cancer patient with bone disease. J Clin Endocrinol Metab 2008; 93(1):2–7.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Grossmann M. Bone and metabolic health in patients with nonmetastatic prostate cancer receiving androgen deprivation therapy — management guidelines. Med J Aust. In Press.Google Scholar
  78. 78.
    Waza M, Adachi H, Katsuno M et al. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med 2005; 11(10):1088–1095.PubMedCrossRefGoogle Scholar
  79. 79.
    Banerji U, O’Donnell A, Scurr M et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demetho xygeldanamycin in patients with advancedmalignancies. J Clin Oncol 2005; 23(18):4152–4161.PubMedCrossRefGoogle Scholar
  80. 80.
    Piccioni F, Roman BR, Fischbeck KH et al. A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor. Hum Mol Genet 2004; 13(4):437–446.PubMedCrossRefGoogle Scholar
  81. 81.
    Caplen NJ, Taylor JP, Statham VS et al. Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference. Hum Mol Genet 2002; 11(2):175–184.PubMedCrossRefGoogle Scholar
  82. 82.
    Takeuchi Y, Katsuno M, Banno H et al. Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy. Muscle Nerve 2008; 38(2):964–971.PubMedCrossRefGoogle Scholar
  83. 83.
    Banno H, Adachi H, Katsuno M et al. Mutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: a pathogenic marker. Annals of Neurology 2006; 59(3):520–526.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Melbourne at Austin HealthHeidelbergAustralia
  2. 2.Department of EndocrinologyAustin HealthHeidelbergAustralia

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